The invention relates to novel monoclonal antibodies and, more particularly, to monoclonal antibodies specific to a unique integrin receptor.
The integrin superfamily of adhesive receptors are transmembrane heterodimeric molecules which function in cell-matrix and cell-cell adhesion [Hynes, Cell 48, 549-554 (1987)]. They are thought to function in adhesion processes by serving as transmembrane links between the extracellular environment and the cytoskeleton. As such they are intimately involved in many complex cell processes including thrombosis, hemostasis, cell maturation, embryogenesis, lymphocyte killing and phagocytosis. The integrins can be roughly classified into three groups: (1) VLA, the very late antigens first described on T lymphocytes, including the fibronectin receptor from human placenta and osteosarcoma cells [Hemler et al., J. Biol. Chem. 262, 3300-3309 (1987)]; (2) cytoadhesins, including the platelet gp IIb/IIIa and the vitronectin receptor [Ginsberg et al., Thromb. Hemostas. 59, 1-6 (1988)]; and (3) LFA-1, Mac-1, p150,95, leukocyte-specific adhesion receptors, including the complement receptor for C3bi (CR3) [Anderson and Springer, Ann. Rev. Med. (1987)]. The heterodimers in each group are comprised of distinct alpha chains non-covalently linked to a common beta chain. Because of this, monoclonal antibodies to the beta chain of each group can be used to classify new receptors as membranes of one or another group within the integrins. As an example, the fibronectin receptor was shown to be a member of the VLA group because it bound A-1A5, a monoclonal antibody which recognizes all VLA beta chains.
In addition to significant structural and sequence homology, the integrins also exhibit ligand-binding similarities. Several of these receptors were first discovered because of their binding to extracellular matrix proteins via an Arg-Gly-Asp (RGD) amino acid sequence in the matrix ligands. The RGD-binding proteins of human neutrophils (PMN) and monocytes has been characterized by affinity chromatography of cell lysates on RGD-Sepharose.RTM. [Brown and Goodwin, J. Exp. Med. 167, 777-793 (1988)]. It was shown that both phagocytes express a heterodimeric receptor distinct from the LFA-1, Mac-1, p150,95 family which exhibits immunological cross-reactivity with gp IIb/IIIa on platelets. Phagocytes undergo a number of important functional changes during recruitment to an inflammatory or infected site. These include changes in the receptors expressed at the plasma membrane, activation of new metabolic pathways, increases in oxygen consumption and the production of reactive oxygen metabolites, and augmentation of phagocytosis. Extracellular matrix proteins have been shown to mediate some of these physiologic changes, especially enhancement of ingestion of opsonized particles by monocytes and macrophages. This enhancement is dependent on recognition of the RGD sequence within these matrix proteins [Brown and Goodwin, supra; Wright and Meyer, J. Exp. Med. 162, 762-767 (1985)]. It is hypothesized that the molecule identified by affinity chromatography on RGD-Sepharose might be the phagocyte receptor involved in extracellular matrix-stimulated ingestion.
For further background information on the RGD sequence and integrins, see Ruoslahti and Pierschbacher, Science 238, 491-497 (1987).